Molecular effects of UVA1 in human skin in vivo

Abstract

The carcinogenic potential of UVA1 (340–400nm) is increasingly being recognised as evidence accumulates of its ability to induce cyclobutane pyrimidine dimers (CPD) ex vivo and in vivo in human beings which if unrepaired may lead to skin cancer. Despite widespread use in phototherapy, tanning lamps and its abundance in terrestrial UVR (ultraviolet radiation), we lack data on its effects on gene expression in human skin. 12 volunteers with skin type I/II were tested for UVR sensitivity: five were given 1 minimal erythema dose (MED) of UVA1 and biopsy samples taken at 6 h and 24 h; an unirradiated control sample was also taken. A further four participants were given 1 MED of UVB and UVA1 and biopsy samples taken at 6 h and 24 h, RNA extracted, converted to cRNA, and hybridised to agilent 44K oligomicroarray plates. After rosetta resolver software analysis, the data were analysed using GeneGo metacore v7 and DAVID.UVA1 upregulated 301 genes at 6 h and 264 genes at 24 h (p<0·05, ≥2 fold change). At 6 h, key gene expression pathways upregulated were inflammation (p=3·46×10−17), apoptosis (p=2·148×10−8), and response to oxidative stress (p=6·457×10−7). CD83 was also dramatically upregulated (positively regulates interleukin 10). At 24 h the top pathway enriched was extracellular matrix remodelling (p=5·549×10−7). A pathway analysis demonstrated that UVB induced the same pathways at 6 h and 24 h as did UVA1; however, functional studies shows that UVB induces a greater upregulation of apoptotic proteins and in terms of genes, similar levels of immunomodulatory genes (CD83, IL10) upregulated.Erythemally equivalent doses of UVA1 induce less apoptosis than UVB but there are similar levels of immunosuppression. Our data suggest that UVA1 might be inducing less of a photoprotective response in vivo in human beings than UVB, which might explain the mechanism of some of our other new findings—that UVA1 CPDs are slower to be repaired at the basal epidermis than UVB CPDs. These findings are important for our understanding of skin cancer. FundingUK Medical Research Council, La Roche- Posay, and Biomedical Research Council.